This is a competitive renewal for a grant that provided the first molecular description of an MHC class I-specific inhibitory receptor (Ly49A) on natural killer (NK) cells which constitute the third major lymphocyte population. Like other lymphocytes, NK cells play significant roles in host defense against tumors and invading pathogens. Humans with selective NK cell deficiencies suffer from recurrent viral and bacterial infections. However, the in vivo development of NK cells is poorly understood. In the last granting period, the investigator's laboratory made significant progress in their specific aims to detail the interactions between Ly49A and its MHC class I ligand. But while producing a Ly49A transgenic mouse as proposed, they generated a mouse that is selectively deficient in NK cells. Unrelated to the function of Ly49A as an inhibitory receptor, these mice appear to have an arrest in NK cell development at an intermediate stage of maturation that is present in wild type mice. Both subpopulations of NK cells are defective in production of IFNgamma. Furthermore, they determined that the transgenic construct is inserted in a gene for a transcription factor. The principal investigator and his laboratory therefore request to focus their efforts in this renewal on the study of NK cell development in vivo. They propose to analyze the transgenic NK cells and their corresponding stage in wild type mice with respect to gene expression, functional responses to cytokines, and their signaling pathways. They will evaluate the role of the transcription factor in NK cell maturation, and investigate other NK cell deficiencies that arise from mutations in transcription factors. These studies will provide significant insight into NK cell development.